Project Summary/Abstract The proposal includes a comprehensive 5-year mentored career development plan for the candidate to transition to an independent investigator who will conduct musculoskeletal research in diabetes and other clinical conditions. The candidate is currently an Instructor in the Department of Orthopedic Surgery at Harvard Medical School and conducts her research at the Center for Advanced Orthopaedic Studies (CAOS) at Beth Israel Deaconess Medical Center (BIDMC). She is well supported by the institution and will devote 100% of her time to her research and career development plan. She will have full access to the facilities at CAOS, the Endocrine Unit at Massachusetts General Hospital (MGH), and at centers and institutions affiliated with Harvard Medical School. The candidate has chosen mentors, a scientific advisory / mentoring committee, and collaborators with a wide array of expertise to help her conduct her work and offer career guidance during her transition to independent research. Her mentor, Dr. Mary Bouxsein, is a leader in the field of biomechanics and skeletal fragility, and is the Director of the CAOS at BIDMC. Her co-mentor, Dr. Marie Demay, conducts work on the biological consequences of hypophosphatemia, and is the Director of the Histology & Histomorphometry core at the Center for Skeletal Research at MGH. The scientific advisory / mentoring committee members (Dr. Clifford Rosen, Dr. Christian Rask-Madsen, and Dr. Paola Divieti Pajevic) have expertise in clinical issues in diabetes, vascular issues in diabetes, and cell culture methods. Further, the candidate has included collaborators (Dr. Elise Morgan, Dr. Ryan Porter, Dr. Ayesha Abdeen, and Dr. Douglas Ayres) to help her with high-resolution imaging, tissue culture, molecular biology techniques, and human subject recruitment. The candidate's project focuses on the causes of skeletal fragility in type 2 diabetes, which are largely unknown. Deficits in bone matrix via the accumulation of advanced glycation end-products and/or microarchitecture have been suggested to be potential mechanisms. The overall goal of this project is to determine the underlying mechanisms of diabetic skeletal fragility with the hypothesis that advanced glycation end-products, microdamage, and cortical porosity will contribute to reduced mechanical properties in diabetic bone. The specific aims are to: 1) determine the contribution of advanced glycation end-products, microdamage, and cortical porosity to diabetic skeletal fragility, 2) determine osteocyte morphology, survival, and gene expression in diabetic bone, and 3) determine the effect of hyperglycemia and non-enzymatic glycation on osteocyte activity. The candidate will be trained in histology, immunohistochemistry, measurement of gene expression, and cell and tissue culture methods to pursue this project. Further, she will be participate in career development activities that cover biostatistics training, grant writing, responsible conduct of research, scientific presentation, and leadership strategies. In summary, this K01 proposal will allow the candidate to gain the experience and training needed to achieve her goal of becoming an independent researcher.